PROJECT SUMMARY ! Inherited axonopathies include the clinically distinct phenotypes, Charcot-Marie-Tooth (CMT) and Hereditary Spastic Paraplegia (HSP), which both cause slowly-progressing, length-dependent axonal degeneration. Both phenotypes are genetically and phenotypically diverse with close to 100 Mendelian genes involved for each thus far. The clinical and genetic overlap between these diseases is increasingly apparent; thus, they can be grouped together as a spectrum of inherited axonopathies and are expected to share common molecular pathologies. It is becoming apparent that despite the spectacular progress in novel gene identification, non-traditional modes of inheritance, risk allele, and modifier genes need to be considered. The focus of this proposal is to characterize the genetic architecture from causative to rare risk alleles more completely by applying exome sequencing and heuristic (variant filtering approaches of exomes/genomes) as well as statistical approaches (rare variant burden analysis) to large patient and control cohorts. We have access to possibly the largest such exome collections in the world. Further, an in silico network biology approach based on known and novel genes (full and partial penetrant) will be used to reveal key cellular pathways that are commonly correlated with inherited axonopathies. By further defining the molecular and genetic etiologies underlying inherited axonopathies, therapeutic targets of broader axonal degeneration may be elucidated. !